Tremor: Etiology, Phenomenology, and Clinical Features

Tremor: Etiology, Phenomenology, and Clinical Features Arif Dalvi, MD, MBA, and Ashvini Premkumar, MD Phenomenology and Classification of Tremor Tremor is defined as an involuntary, rhythmic, oscillatory movement produced by either synchronous or alternating contractions of antagonist muscles.1 Tremors can be classified by their distribution and frequency, as well as by the “state of activity.” This state of activity refers to whether the tremor occurs at rest or with action and this distinction is clinically important. The following definitions may be applied2: 1. Rest tremor is observed when the affected body part is supported against gravity and is not voluntarily activated. 2. Action tremor is observed during voluntary contraction of muscles and can be further subdivided into postural, kinetic, task-specific, or isometric tremors a. Postural tremor is seen during voluntary maintenance of a position against gravity (eg, holding hands outstretched in front of one’s body). b. Kinetic tremor occurs during any aspect of voluntary movement. It can be present when the movement begins, during the course of movement, and as the target is reached (intention tremor). c. Task-specific tremor is a specific type of kinetic tremor that occurs primarily during the execution of a certain task, such as writing or singing. d. Isometric tremor is present during muscle contraction that is not accompanied by a change in position of body part (such as maintenance of tightly squeezed fist). Tremor subtypes and common etiologies are listed in Table 1.

Etiology of Tremor Physiological Tremor This is a normal finding that is seen as a fine action tremor. The term enhanced physiological tremor (EPT) refers to a state where the baseline Dis Mon 2011;57:109-126 0011-5029/2011 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2011.02.004 DM, March 2011

109

TABLE 1. Tremor subtypes and typical etiologies Definition

Comments

Typical Etiologies

Associated Findings

Rest

Type

With limb completely supported by gravity

“Pill rolling tremor” with hands in lap

Bradykinesia, rigidity, stooped posture, shuffling or freezing gait

Postural

Limb voluntarily maintained against gravity

Outstretched posture of hands or pouring from a cup

Parkinson’s disease and Parkinsonism, Wilson’s disease Essential tremor, FXTAS

Kinetic

During any voluntary movement

Finger-to-nose testing will show terminal tremor

Cerebellar tremor, multiple sclerosis, Wilson’s disease

Task-specific

Only occurs during specific activity

Demonstrate activity that triggers tremor

Writer’s cramp, occupational tremor

Holmes (rubral)

Mixed rest, postural and kinetic tremor

Rest tremor increases with posture and with action

Midbrain and thalamic lesions

Usually monosymptomatic, but mild gait ataxia may be seen, especially with FXTAS Ataxia, dysmetria, dysdiadokinesia, optic disk changes in multiple sclerosis, KayserFleisher rings in Wilson’s disease Dystonic posturing may be observed when performing or initiating the activity Cranial nerve findings (especially cranial nerve 3), skew deviation of the eyes

tremor is exacerbated by anxiety, metabolic disorders, such as hyperthyroidism, or agents, such as ␤-adrenergic receptor agonists and caffeine (Table 2).2 The frequency of EPT ranges from 8 to 12 Hz and is affected by the mechanical properties of the oscillating limb. Unlike essential tremor (ET), the frequency of EPT can be reduced by mass loading, for example, with a lead-weighted wristband.

Essential Tremor This is by far the most common form of a pathologic tremor. In its classic state, an ET has been described as a postural and kinetic action tremor that is typically bilateral, involving the arms, head, and/or voice. It may also spread to involve the legs, chin, and trunk.3,4 Isolated head tremor may also occur, but in such cases cervical dystonia is also a diagnostic possibility, particularly if there is a directional component to 110

DM, March 2011

TABLE 2. Causes of enhanced physiological tremor Stress-induced Sympathomimetic drugs

Other drugs and toxins

Endocrine disturbance

Anxiety, emotion, fatigue, exercise, fever ␤-Adrenergic agonists, amphetamines, cocaine, dopaminergic drugs, methylxanthines (coffee, tea, theophylline) Valproic acid, neuroleptic drugs, tricyclic antidepressants, lithium, cyclosporine, arsenic, bismuth, bromine, mercury, lead, ethanol withdrawal Thyrotoxicosis, hypoglycemia, adrenocorticosteroids, pheochromocytoma

the tremor. Rest tremor may occasionally be seen in elderly people with longstanding ET; however, the superimposition of Parkinson’s disease (PD) or other forms of parkinsonism is also a possibility. It is also important to ensure that the body part being examined is completely supported against gravity as partial activation of muscles can give a mistaken impression of a rest tremor.2 ET in the classic form presents as a monosymptomatic disorder. However, other neurological signs may be present. In part this may be because ET is a common disorder and may coexist with other neurological disorders. However, the discovery of ET as part of the fragile X permutation carrier syndrome as well as the findings of Lewy Body pathology in some cases of ET5 has led to the recognition that ET may present in combination with other neurological symptoms and should be considered under the rubric of a neurodegenerative disease.6 ET can be either hereditary or sporadic. The overall population prevalence varies between 4 and 39 cases per 1000 people.7 The frequency of the tremor in ET typically ranges from 4 to 10 Hz. While the frequency of the tremor stays relatively constant in a particular individual, the amplitude may vary depending on the position of the involved extremity.2

Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) Expansions of the CGG repeats in the fragile X mental retardation 1 gene led to clinical manifestations based on the number of repeats. More than 200 repeats are associated with developmental delay and autism. However, repeats in the premutation range (55-200) are associated with a tremor syndrome resembling ET and additional symptoms, including cerebellar gait ataxia, frontal executive dysfunction, and global brain atrophy. Other associated findings may include mild parkinsonism, peripheral neuropathy, depression and anxiety, and autonomic dysfuncDM, March 2011

111

tion.8 Cardiac dysfunction, hypothyroidism, and diabetes are more common in persons with FXTAS. Age of onset is usually in the seventh decade and it occurs primarily in men owing to the protective effect of the second X chromosome in females. The rare affected females with FXTAS present with a less severe form. Approximately 1 in 260 females and 1 in 813 males are premutation carriers. The predicted lifetime risk in men is estimated at 1 in 8000. Hyperintensity in the middle cerebellar peduncle (MCP) on T-2 weighted magnetic resonance imaging (MRI) imaging (MCPs sign) is a useful radiological clue to diagnosis.9

Parkinson’s Disease The “pill rolling” rest tremor is the classic description of the tremor in PD. However, in practice, various combinations of rest and postural tremors can be seen.2 Reemergent tremor is a variation of the tremor seen in PD that can create confusion with the typical postural tremor seen in ET. While in most cases the rest tremor subsides when the hands are held outstretched, a postural tremor may reemerge after a short duration. The latency of this tremor is of the order of 8-10 seconds as opposed to ET, where the latency from time the hands are held outstretched to onset of tremor ranges from 0 to 2 seconds. Of note, in approximately 10-30% of cases of PD, tremor may be completely absent.10 Typically, the tremor in PD is unilateral in onset and may remain so for several years in contrast to ET. Further clues to a diagnosis of PD tremor include the presence of bradykinesia and rigidity. Often “cogwheel rigidity” is described in PD, which refers to the combination of a palpable tremor superimposed on underlying lead pipe rigidity. Having the patient perform rapid alternating movements with the contralateral hand may help bring out cogwheel rigidity in mild cases. Tremor is the presenting complaint in 60-70% of cases and may remain the main manifestation of the condition for several years without development of significant bradykinesia or gait disorder, a condition referred to as benign tremulous PD.11 The location of the tremor generator in PD is poorly understood and tremor severity correlates poorly with the nigrostriatal dopaminergic deficit.12 Loss of particular subgroups of mesencephalic neurons may determine the presence and severity of tremor in PD.13 In particular, neurodegeneration of the retrorubral area (A8) is more prominent in the tremor-predominant variant of PD. In contrast, the lateral substantia nigra (A9) shows more significant degeneration in the akinetic-rigid form of PD. Serotonin systems may also play a role in tremor generation. Reduced 5-HT1A binding has been correlated with tremor but not rigidity or bradykinesia.14 Possible locations of the central oscillator responsible 112

DM, March 2011

for PD tremor include the cerebellum, the thalamus, the globus pallidus, and the subthalamic nucleus.15 During microelectrode recording for deep brain stimulation surgery, “tremor cells” can be demonstrated in the ventrointermedius nucleus of the thalamus, the globus pallidus, and the subthalamic nucleus.16 It is postulated that these cells form an unstable oscillating network that is responsible for the tremor. Lesioning in these nuclei or deep brain stimulation techniques may disrupt this network, resuming the normal unsynchronized activity, which leads to improved tremor control.15

Cerebellar Tremor Cerebellar tremor is typically a proximal action tremor of large amplitude with low frequency (typically in the 3- to 5-Hz range). Lesions of the deep cerebellar nuclei or outflow pathways in the superior cerebellar peduncle result in this tremor. The intention component of kinetic tremor is often characteristic of cerebellar tremor. The tremor has a tendency to increase as the target is approached, which is referred to as a terminal tremor.1 However, various types of postural tremor have also been described. Titubation refers to a postural tremor of the head and trunk—most pronounced when the patient is standing.2 It is often accompanied by other signs of cerebellar disease, such as ataxia, dysmetria, and dysdiadokinesis. The most common causes of cerebellar tremor include multiple sclerosis, mass lesions, vascular and degenerative diseases. Toxic cerebellar degeneration may occur because of alcohol abuse or drug-toxicity from drugs, such as anticonvulsants, neuroleptics, or lithium. The tremor in these cases tends to be bilateral. In contrast, tremor from a structural lesion, such as a mass, infarct, or plaque tends to be unilateral.2 Cerebellar tremor may occasionally be a delayed sequel to a head injury, either because of direct injury to the dentate nucleus or because of shear injury to cerebellar axons in the outflow pathways.17 The inherited spinocerebellar ataxias18 and paraneoplastic syndromes19 are other important causes of cerebellar tremor. The cerebello-dentato-rubro-thalamic circuit is critical for normal movement. Lesions in the deep lateral cerebellar nuclei and their outflow pathways up to the red nucleus can cause cerebellar tremor. Lesions of the red nucleus and beyond cause Holmes tremor. Lesions proximal to the decussation of the outflow pathways result in ipsilateral tremor and distal lesions result in contralateral tremor. Injury to the cerebellar cortex itself does not cause tremor.20 It is uncommon for cerebellar tremor to be an DM, March 2011

113

isolated finding and associated findings, including ataxia and gait disorder, are usually observed.2

Holmes Tremor Holmes tremor (synonymous with the terms rubral tremor or midbrain tremor) refers to a combination of rest, postural, and action tremors due to midbrain lesions. Common causes include strokes, tumors, multiple sclerosis, or vascular malformations. As the lesion is typically in the vicinity of the red nucleus (which is part of the cerebellar outflow tract), the tremor phenotype is similar to that of a cerebellar tremor in that the tremor tends to be irregular with a low frequency.21 The tremor has a static and dynamic component. The static component consists of a coarse tremor with a frequency of 3-5 Hz that increases with attempts at inhibition. The dynamic component consists of an irregular intention tremor similar to that seen in MS. Associated findings may include diplopia, ptosis, oculomotor palsies, hemiparesis, hemianopia, and parkinsonian features.21 A key anatomic observation is the sparing of corticospinal tracts. The initial descriptions by Sir Gordon Holmes in 1904 suggested that involvement of the red nucleus was a key anatomic component, leading to the term “rubral tremor,” although Holmes himself did not use this term. However, the advent of improved imaging techniques demonstrated that this tremor could also be found with lesions in other midbrain structures as well as the thalamus. Hence the term “rubral tremor” has been abandoned in favor of the term Holmes tremor.1

Dystonic Tremor Dystonia is characterized by involuntary, sustained, patterned muscle contractions of opposing muscles resulting in twisting movements, abnormal postures, or both. A dystonic tremor refers to a tremor that occurs in a body part that is simultaneously affected by dystonia.2 The tremor is irregular and jerky in nature interrupted with sustained dystonic spasms. Dystonic tremor is typically position sensitive. For example, when the patient is allowed to move the affected body part to the position of maximal pull, the null point is reached and tremor often ceases. The tremor may be relieved with complete rest or touching the affected body part (geste antagoniste). The tremor may be the initial sign of an evolving dystonia in the region.22 The pathophysiology of dystonic tremor is poorly understood. Head tremor in cervical dystonia has been studied with electromyographic (EMG) polygraphy. Two types of tremor may appear separately or in coexistence, an ET-like tremor and a dystonic tremor. The ET-like tremor 114

DM, March 2011

has a higher frequency with a peak at 9-11 Hz, whereas the dystonic tremor has a peak at about 5 Hz. The dystonic tremor has a characteristic null point and is subject to modification by a geste antagoniste.23 Because of the variable nature of dystonic tremor, it may be confused with psychogenic tremor. The clinical features of psychogenic tremor are discussed below. The coherence entrainment test has been proposed as a way to distinguish these 2 tremors. This is a quantified electrophysiological entrainment test performed on accelerometer or surface EMG tremor signals. While a small study suggested a high level of accuracy, the test is not readily available.24

Task-Specific Tremor Task-specific tremor is a kinetic tremor that appears during the performance of highly skilled, learned motor tasks. It may also be referred to as occupational tremor. The most frequent task-specific tremor is a primary writing tremor, which occurs specifically during the act of writing.25 Two types of primary writing tremor are known to occur. The first appears only during writing, while the second occurs when the hand adopts a writing posture and is known as position-specific tremor. Some patients with this form of tremor may also have an associated focal dystonia. A large variety of presentations of such tremor may occur with other repetitive, frequently performed movements, such as in speaking, singing, or playing a musical instrument. The tremor may resemble ET or a dystonic tremor or have features common to both on clinical examination as well as on EMG analysis.23 It is unclear why such a tremor only occurs during a narrow range of possible movements and is specific to repetitive tasks. A central disorder of motor control may be present since functional imaging studies in these cases show the representation of the affected body part in the primary sensory cortex is markedly disordered. Somatosensory cortical representation is also abnormal in dystonia, which is another overlap between task-specific tremor and dystonia. Epidemiologic data show a higher risk for those musicians who play instruments requiring a higher degree of fine-motor skills, and, where workload differs across hands, focal dystonia is seen more often in the more intensely used hand.26

Orthostatic Tremor A primary orthostatic tremor (OT) typically involves the legs and trunk and is present when standing still. It generally improves with walking.27 There may be a latency period and the patient may have to stand in a stationary position for 3 to 5 minutes before the tremor will be manifest. DM, March 2011

115

OT is more common in women and usually presents in the sixth or seventh decade. The frequency is greater than other tremors, in the 13- to 18-Hz range. The patient often experiences the tremor as a feeling of unsteadiness. The tremor can also be palpated or auscultated with a stethoscope. While present chiefly during standing, OT may also be precipitated by isometric contraction of the upper limbs, suggesting that it is more likely related to isometric force control rather than regulation of stance. Cranial nerve musculature has also been shown to be involved in OT and all the muscles involved exhibit a high degree of coherence in terms of the occurrence of the tremor.28,29 Postural tremor of the hands is often present and patients with OT may have family members with ET, suggesting that OT is a variant of ET. However, in contrast with ET, this form of tremor does not have a high degree of response to alcohol or ␤-adrenergic blockade and has a much more rapid frequency. OT may occasionally occur in the setting of PD as well and may respond to dopaminergic medications. Orthostatic myoclonus is a similar condition but appears to be a distinct disorder. Patients complain of leg jerking during upright posture. There is a gradual decline of gait, often described as “apraxia” or “gait initiation difficulty” in these patients.30

Neuropathic Tremor Peripheral nerve disorders can cause tremors. One of the best documented etiologies in this setting is Charcot–Marie–Tooth disease, which is characterized by foot deformities, weakness, and atrophy affecting the anterior compartment muscles in the lower leg leading to the classically described “Inverted Coke Bottle” appearance of the legs. An autosomaldominant peripheral neuropathy is one of the defining features of this syndrome and is associated with a postural tremor that resembles ET.31 Tremor is present in about a third of patients with Charcot–Marie–Tooth disease and can occur in both the demyelinating (type 1) and the axonal (type 2) forms.32 Tremor may also be seen in patients with mild to moderate forms of spinal muscular atrophy and in Kennedy disease. Gynecomastia and facial and tongue fasciculation are clues to the latter diagnosis.33

Wilson’s Disease Wilson’s disease is an important diagnostic consideration, especially in an adolescent or young adult.34 Tremor is a common feature of Wilson’s disease and can present as a rest tremor or postural tremor or a combination. There may also be a “wing beating” tremor when the arms 116

DM, March 2011

are held in front of the body with the arms flexed at the elbows. The presence of parkinsonian features, such as rigidity or bradykinesia, can lead to diagnostic confusion. Dystonia may also be present as an associated feature. Gait disorders, in the form of either a broad-based cerebellar gait or a bradykinetic parkinsonian gait, are often seen. Kayser-Fleischer rings may be seen in the cornea on direct examination or by slit-lamp examination and are present in most patients with neurological disease.35

Tremor Due to Infectious Diseases Infectious diseases can be the primary cause or exacerbating factor for tremor and other movement disorders.36 Both ET-like presentations and secondary parkinsonism can be seen. Holmes tremor and cerebellar tremor may be seen with midbrain lesions. Tuberculomas and toxoplasmosis of the midbrain have been associated with Holmes tremor.21 Meningitis and encephalitis of any etiology can lead to tremor. Gastrointestinal infections, including Helicobacter pylori and Escherichia coli of the O157:H7 strain, have been associated with tremor.37 Syphilis and HIV infections can lead to a variety of movement disorders, including secondary parkinsonism and isolated tremor. Tremor, ataxia, and loss of fine motor coordination can be features of the AIDS-dementia complex.36 When a movement disorder is seen in the setting of HIV, it is particularly important to rule out treatable opportunistic infections, such as toxoplasmosis, as well as a mass lesion. While myoclonus is the more common movement disorder seen in Creutzfeldt–Jakob disease, tremor may also be a manifestation.38 Tremor and ataxia may also be seen in acute disseminated encephalomyelitis.39 West Nile infections can present with a variety of neurological manifestations with tremor being particularly common. In a survey of 39 suspected cases, the 16 seropositive individuals showed tremor (15), myoclonus (5), and parkinsonism (11).40

Posttraumatic Tremor Posttraumatic tremor is a challenging diagnosis with poorly defined criteria. The concept of tremor following a central injury is more accepted than a peripherally induced tremor.41,42 Retrospective studies suggest that following closed head injury posttraumatic tremor is the second most common movement disorder after dystonia. Posttraumatic tremor most often follows as a delayed sequel to severe head trauma and there may be a significant delay between the injury and development of symptoms. In a survey of 289 severely head injured children tremor prevalence was DM, March 2011

117

estimated to be 45%.43 The tremor appeared at any time within the first 18 months after injury and in at least half the cases it subsequently subsided spontaneously.44

Drug-Induced Tremor A careful drug history is mandatory when evaluating tremor. Tremor is a side effect of a number of medications and the list grows as more are brought to market.45 Tremors may also occur during withdrawal from certain drugs and alcohol. A postural tremor is most commonly seen; however, resting and intention tremors can occur as well.46 Medications that can frequently cause tremor or have a particular mechanism that casts light on the pathophysiology of tremor are reviewed below. Table 3 is a summary of pharmacotherapeutic agents that may cause tremor. As would be expected from the pathophysiology of tremor, and the effectiveness of ␤-blockers as treatment, sympathomimetic drugs can often cause tremor. ␤2-Agonists are often used in inhaled or oral forms as bronchodilators for the treatment of asthma. Tremor has been commonly reported in 2-14% of patients on bronchodilators.47 While the precise mechanism is unknown, it is believed that ␤-agonists may act through a peripheral mechanism at the level of muscle. Adrenergic stimulation may create an imbalance between fast- and slow-twitch muscle fibers in the extremities that leads to tremor.48 Neuroleptic medications can lead to a drug-induced parkinsonism through the mechanism of blockade of central dopaminergic receptors. Rest tremor and bradykinesia are common manifestations. In a study of older neuroleptics tremor was noted in 35% of over 3000 patients as the initial symptom of drug-induced parkinsonism.49 While the atypical neuroleptics are less common offenders, tremor and parkinsonism have been reported with virtually every neuroleptic medication.50 Metoclopramide is a dopamine receptor antagonist used to treat nausea and gastroparesis. Long-term use of metoclopramide has been associated with tremor, parkinsonism, and tardive dyskinesia.51 In 2009, the U.S. Food and Drug Administration issued a black box warning regarding long-term or high-dose use of this medication because of the risk of developing tardive dyskinesia.52 Reserpine and tetrabenazine, which has been recently approved for the treatment of chorea in Huntington’s disease, are dopamine depleting agents that can also cause tremor.53 Other drugs used in psychiatry that can produce postural tremor include lithium, valproic acid, lamotrigine, antidepressants, and neuroleptics.54 Drug-induced postural or kinetic tremors may respond to ␤-blockers, such as propranolol. 118

DM, March 2011

TABLE 3. Pharmacotherapeutic agents associated with tremor46-53 Drug Class Antiarrythmics

Examples

Type of Tremor

Mechanism and Comments

Amiodarone Mexiletine Procainamide Co-trimaxazole Ciprofloxacin Amitryptilline SSRIs

Postural

Unknown

Rest and postural Postural

Unknown

Antiepileptics

Valproic acid Lamotrigine Tigabine

Postural

Antivirals

Vidarabine Acyclovir Amphotericin-B Albuterol Salmeterol Cisplatin Cytarabine Ifosfamide Tamoxifen Cimetidine Metoclopramide Epinephrine Thyroxine Cyclosporin Interferon-␣ Tacrolimus Lithium

Postural and intention Postural Postural and intention Postural and intention

Antibiotics Antidepressants

Antifungals Bronchodilators Chemotherapeutics

Gastrointestinal drugs Hormones Immunosuppressants

Mood stabilizers Neuroleptics and dopamine-depleting agents

Haldol Thorazine Reserpine Xenazine

Rest and action Postural and intention Postural and intention Postural and intention Rest tremor

Unknown May be marker for serotonergic syndrome with SSRIs, may also be seen with withdrawal from SSRIs Unknown Combination of valproic acid and lamotrigine more likely to cause tremor Unknown Unknown Increased sympathetic drive Cerebellar degeneration with cisplatin, unknown for others

Metoclopramide may cause drug-induced parkinsonism Increased sympathetic drive Unknown Interferon-␣ may suppress dopaminergic system Rest tremor can represent drug-induced parkinsonism Tremor may be part of druginduced parkinsonism Atypical neuroleptics may also cause tremor

Neuroleptic-induced rest tremor may respond to an anticholinergic medication. Switching to an atypical neuroleptic may be appropriate.

Psychogenic Tremor Psychogenic tremor is the most common psychogenic movement disorder. Differentiating between psychogenic tremor and organic tremors can be challenging. The diagnosis is made based on the history as well as careful observation of the tremor.55 DM, March 2011

119

Psychogenic tremors usually have an abrupt onset with maximal disability also often seen at the onset. The clinical course is marked by variability and may include spontaneous remissions and recurrences. Tremors may affect the wrists, elbows, and shoulders but rarely the fingers.56 The amplitude and frequency of psychogenic tremors are variable in response to attention or distraction. By contrast, with organic tremors, although the amplitude may change with stress or emotions, the frequency tends to stay constant. Psychogenic tremors also commonly exhibit an entrainment phenomenon.57 The frequency of the tremor in a limb may change to match the frequency of voluntary tapping in another limb. Psychiatric evaluation may not always be contributory but depression and other psychosomatic conditions are common. Psychogenic tremors typically do not respond to conventional antitremor medications but may respond to antidepressants or psychotherapy. Koller and colleagues provided the following diagnostic criteria in the diagnosis of psychogenic tremors: (1) abrupt onset; (2) static course; (3) spontaneous remission; (4) difficulty in classification (with various combinations of rest, postural, and kinetic tremors); (5) selective disability; (6) variability with changing amplitudes and frequency; (7) unresponsiveness to antitremor drugs; (8) increasing tremor with attention; (9) lessening tremor with distractibility; (10) responsiveness to placebo; (11) absence of other neurological signs; (12) remission with psychotherapy.55 A simplified diagnostic scheme is given in Table 4.

Clinical Approach to the Diagnosis of Tremor The diagnosis of tremor relies on history and examination with imaging studies and laboratory tests playing a secondary role in most cases. Key questions to ask during history taking include age at onset, mode of onset (sudden or gradual), first site affected, sequence of subsequent sides affected, and rate of progression. Family history of tremor, PD, or other neurological disorder should also be elucidated. Careful medication review is important and the responsiveness to alcohol and medical treatment should also be determined.

TABLE 4. “ABC” of psychogenic tremor ● ● ● ● ● 120

Abrupt onset often with maximal disability at onset Bizarre presentation not fitting with typical syndromes Changing amplitude and frequency during or between visits Distraction and attention can change tremor Entrainment phenomenon may be seen DM, March 2011

The physical examination should determine the location and severity of tremor, the state of activity when tremor is present, and additional findings, such as bradykinesia, rigidity, gait, and postural changes, which suggest the presence of parkinsonism; ataxia, and cerebellar findings indicative of multiple sclerosis; and dystonia, where the tremor will often have a directional component.2 The tremor should be examined in various positions and states. In the upper extremity the tremor should be examined while resting in the patient’s lap or fully supported by the arm of a chair to elicit rest tremor. Examining the tremor with the hands outstretched will demonstrate postural tremor and the reemergent tremor of PD. Finger-to-nose testing will demonstrate kinetic tremors, with increase toward the terminus of the movement being a feature of terminal tremor. The upper extremity should also be held in various positions of rotation and with the elbows bent to look for a directional component, which is a characteristic of dystonic tremor. The patient should be observed while providing a handwriting sample as well as while drawing an Archimedes’ spiral. A large spiral with jagged handwriting is typical of ET (Fig 1A), while a micrographic spiral with decrement in the size of the letters toward the end of the sentence while writing is seen in PD (Fig 1B). Other findings that should be looked for include the presence of Kayser-Fleisher rings in the cornea and hepatomegaly, which indicate Wilson’s disease, changes in the optic disk that may occur with multiple sclerosis, difficulties with balance and coordination suggestive of a spinocerebellar ataxia, and the presence of a peripheral neuropathy or distal muscle atrophy, which are hallmarks of Charcot–Marie–Tooth disease.

FIG 1. (A) Handwriting and Archimedes’ spiral in essential tremor. Note jagged edges to handwriting and large and loose spiral. (B) Handwriting and Archimedes’ spiral in Parkinson’s disease. Note micrographic handwriting and spiral. DM, March 2011

121

Laboratory Workup and Imaging Studies in a Tremor Patient The extent of the investigations depends on the diagnostic certainty on clinical grounds. Thyroid function tests and routine metabolic tests are usually ordered as screening tests. Screening tests for Wilson’s disease include serum ceruloplasmin, which is usually low, and measurement of 24-hour urine copper, which is increased. Further workup includes a slit-lamp examination to look for Kayser-Fleischer rings, which are present in most patients with neurological symptoms.35 An MRI of the brain is usually ordered to rule out structural etiologies, such as multiple sclerosis or a focal midbrain lesion that can lead to a Holmes’ tremor. When a parkinsonian condition, such as PD or multiple system atrophy (MSA), is suspected, then a positron-emission tomography or singlephoton emission computed tomography scan is a consideration, but typically these tests are reserved for cases where the diagnostic uncertainty remains after a careful clinical evaluation and failure to respond to a therapeutic trial of dopaminergic medications. EMG and nerve conduction tests are helpful for tremor disorders associated with a peripheral neuropathy, such as Charcot–Marie–Tooth disease. When a combination of tremor and neuropathy is found, supplementary investigations to consider include serum protein electrophoresis, urinary Bence-Jones protein, and a porphyrin screen. The analysis of tremor frequency with accelerometers and surface EMG can be useful to characterize a tremor but has a limited practical role in diagnosis. Specific imaging findings on the MRI of the brain may be seen in some tremor subtypes. The FXTAS syndrome is associated with MRI changes that include atrophy of the cerebrum, cerebellar cortex, corpus callosum, and pons. The cerebral and cerebellar white matter have increased T2 and decreased T1 signal intensity. A distinctive abnormality of the MCPs is a hallmark of FXTAS, with increased T2 signal in about 60% of affected men and 13% of affected women.9 The MRI of the brain does not provide diagnostic clues in PD and as a rule is unhelpful in the diagnosis of parkinsonism. However, if present, characteristic radiological abnormalities can be helpful in the diagnosis of parkinsonism. These include midbrain atrophy in progressive supranuclear palsy, atrophy of the pons and cerebellum as well as the MCPs in olivoponto-cerebellar atrophy, and focal cortical atrophy in corticobasal ganglionic degeneration.58 Signal hyperintensities within the pons and MCPs in MSA may occasionally result in the “‘hot cross bun’” sign, although this finding is not exclusive to MSA.59 122

DM, March 2011

TABLE 5. Distinguishing essential tremor from Parkinson’s disease Feature Typical age of onset Clinical course Type of tremor

Tremor frequency Associated findings Family history

Possible genetic associations Response to treatment

Surgical target

Essential Tremor Bimodal: childhood and elderly Slow, relatively benign progression Postural and kinetic

4-12 Hz Usually none, but mild dementia or gait ataxia may be seen Present in about 50%

LINGO-1, fragile-X, 3q13 (ETM1), 2p22 (ETM2) Propranolol and primidone most effective, with topiramate and gabapentin as second line Vim nucleus of thalamus

Parkinson’s Disease Age 55-65, rarely young-onset/juvenile Increasing disability due to tremor as well as associated symptoms Typically a rest tremor, but postural and reemergent tremor may occur. Tremor may be absent in about 30% of PD cases 3-5 Hz, occasionally faster Bradykinesia, rigidity, posture and gait changes, cognitive disorders Mostly sporadic, although may occasionally show autosomaldominant or -recessive inheritance ␣-Synuclein, Parkin, LRRK2, DJ-1, PINK1 Levodopa, dopamine agonists, MAO-B inhibitors, amantadine, anticholinergics

Subthalamic nucleus most common

Distinguishing Essential Tremor and Parkinson’s Disease The typical presentations of PD and ET are usually easy to distinguish based on historical features and physical findings (Table 5). In most cases, ET presents as a monosymptomatic postural and kinetic tremor as opposed to PD, where rest tremor is the hallmark presentation and the tremor is accompanied at the very least by bradykinesia. However, there can be both clinical and pathologic overlap between ET and PD. Preexisting ET may represent a risk factor for subsequent development of PD, and such patients tend to have a tremor-dominant subtype.60 In a population-based cohort study of 3813 older people (including ET cases and controls) in central Spain patients with ET were 4 times more likely than controls to develop incident PD during prospective follow-up of a median of 3.3 years.61 Altropane is a molecular-imaging agent that binds to the dopamine transporter protein found on dopaminergic neurons. Parkinsonian syndromes, including PD, result in a decreased number of dopaminergic neurons. These DM, March 2011

123

patients are expected to have fewer dopamine transporter proteins than patients with tremor from a nonparkinsionian etiology, such as ET. Altropane binding, as visualized by single-photon emission computed tomography imaging, may thus be able to distinguish PD from ET.62

REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 124

Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13(Suppl 3):2-23. Bain PG. Parkinsonism and related disorders. Tremor. Parkinsonism Relat Disord 2007;13(Suppl 3):S369-74. Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41:234-8. Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential tremor. Brain 1994;117:805-24. Louis ED, Faust PL, Vonsattel JP, et al. Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 2007;130:3297-307. Louis ED. Essential tremor: evolving clinicopathological concepts in an era of intensive post-mortem enquiry. Lancet Neurol 2010;9:613-22. Elble RJ. Report from a U.S. conference on essential tremor. Mov Disord 2006;21:2052-61. Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med 2009;57:830-6. Berry-Kravis E, Abrams L, Coffey SM, et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord 2007; 22:2018-30. Hughes AJ, Daniel SE, Blankson S, et al. A clinicopathologic study of 100 cases of Parkinson’s disease. Arch Neurol 1993;50:140-8. Josephs KA, Matsumoto JY, Ahlskog JE. Benign tremulous parkinsonism. Arch Neurol 2006;63:354-7. Vingerhoets FJ, Schulzer M, Calne DB, et al. Which clinical sign of Parkinson’s disease best reflects the nigrostriatal lesion? Ann Neurol 1997;41:58-64. Paulus W, Jellinger K. The neuropathologic basis of different clinical subgroups of Parkinson’s disease. J Neuropathol Exp Neurol 1991;50:743-55. Jellinger KA. Post mortem studies in Parkinson’s disease—is it possible to detect brain areas for specific symptoms? J Neural Transm Suppl 1999;56:1-29. Bergman H, Deuschl G. Pathophysiology of Parkinson’s disease: from clinical neurology to basic neuroscience and back. Mov Disord 2002;17(Suppl 3):S28-40. Brodkey JA, Tasker RR, Hamani C, et al. Tremor cells in the human thalamus: differences among neurological disorders. J Neurosurg 2004;101:43-7. Krauss JK, Tränkle R, Kopp KH. Post-traumatic movement disorders in survivors of severe head injury. Neurology 1996;47:1488-92. Manto MU. The wide spectrum of spinocerebellar ataxias (SCAs). Cerebellum 2005;4:2-6. Mehta SH, Morgan JC, Sethi KD. Paraneoplastic movement disorders. Curr Neurol Neurosci Rep 2009;9:285-91. Elble RJ. Central mechanisms of tremor. J Clin Neurophysiol 1996;13:133-44. DM, March 2011

21.

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

38. 39. 40. 41. 42. 43. 44. 45.

Dalvi A. Holmes tremor. In: Lyons KE, Pahwa R, editors. Handbook of Essential Tremor and Other Tremor Disorders. Boca Raton, FL: Taylor & Francis, 2005. p. 243-50. Jedynak CP, Bonnet AM, Agid Y. Tremor and idiopathic dystonia. Mov Disord 1991;6:230-6. Deuschl G. Dystonic tremor. Rev Neurol Paris 2003;159:900-5. McAuley J, Rothwell J. Identification of psychogenic, dystonic, and other organic tremors by a coherence entrainment test. Mov Disord 2004;19:253-67. Bain PG, Findley LJ, Britton TC, et al. Primary writing tremor. Brain 1995; 118(6):1461-72. Altenmüller E, Jabusch HC. Focal dystonia in musicians: phenomenology, pathophysiology, triggering factors, and treatment. Med Probl Perform Arts 2010;25:3-9. Heilman KM. Orthostatic tremor. Arch Neurol 1984;41:880-1. Koster B, Lauk M, Timmer J, et al. Involvement of cranial muscles and high intermuscular coherence in orthostatic tremor. Ann Neurol 1999;45:384-8. Boroojerdi B, Ferbert A, Foltys H, et al. Evidence for a non-orthostatic origin of orthostatic tremor. J Neurol Neurosurg Psychiatry 1999;66:284-8. Glass GA, Ahlskog JE, Matsumoto JY. Orthostatic myoclonus: a contributor to gait decline in selected elderly. Neurology 2007;68:1826-30. Cardoso FE, Jankovic J. Hereditary motor-sensory neuropathy and movement disorders. Muscle Nerve 1993;16:904-10. Keller MP, Chance PF. Inherited peripheral neuropathy. Semin Neurol 1999; 19:353-62. Meriggioli MN, Rowin J, Sanders DB. Distinguishing clinical and electrodiagnostic features of X-linked bulbospinal neuronopathy. Muscle Nerve 1999;22:1693-7. Brewer GJ, Fink JK, Hedera P. Diagnosis and treatment of Wilson’s disease. Semin Neurol 1999;19:261-70. Huster D. Wilson disease. Best Pract Res Clin Gastroenterol 2010;24:531-9. Barton B, Zauber SE, Goetz CG. Movement disorders caused by medical disease. Semin Neurol 2009;29:97-110. Hamano S, Nakanishi Y, Nara T, et al. Neurological manifestations of hemorrhagic colitis in the outbreak of Escherichia coli O157:H7 infection in Japan. Acta Paediatr 1993;82:454-8. Maltête D, Guyant-Maréchal L, Mihout B, et al. Movement disorders and Creutzfeldt–Jakob disease: a review. Parkinsonism Relat Disord 2006;12:65-71. Gabis LV, Panasci DJ, Andriola MR, et al. Acute disseminated encephalomyelitis: an MRI/MRS longitudinal study. Pediatr Neurol 2004;30:324-9. Sejvar JJ, Haddad MB, Tierney BC, et al. Neurologic manifestations and outcome of West Nile virus infection. JAMA 2003;290:511-5. Krauss JK, Jankovic J. Head injury and posttraumatic movement disorders. Neurosurgery 2002;50:927-39. Jankovic J. Peripherally induced movement disorders. Neurol Clin 2009;27:821-32. Johnson SL, Hall DM. Post-traumatic tremor in head injured children. Arch Dis Child 1992;67:227-8. Krauss JK, Wakhloo AK, Nobbe F, et al. Lesion of dentatothalamic pathways in severe post-traumatic tremor. Neurol Res 1995;17:409-16. Morgan JC, Sethi KD. Drug-induced tremors. Lancet Neurol 2005;4:866-76.

DM, March 2011

125

46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59.

60.

61.

62.

126

Susatia F, Fernandez HH. Drug-induced parkinsonism. Curr Treat Options Neurol 2009;11:162-9. Smucny J, Flynn C, Becker L, et al. Beta2-agonists for acute bronchitis. Cochrane Database Syst Rev 2001;1:CD001726. Marsden CD, Foley TH, Owen DA, et al. Peripheral beta-adrenergic receptors concerned with tremor. Clin Sci 1967;33:53-65. Ayd F. A survey of drug-induced extrapyramidal reactions. JAMA 1961;175: 1054-60. Haddad PM, Dursun SM. Neurological complications of psychiatric drugs: clinical features and management. Hum. Psychopharmacologie 2008;23(Suppl 1):15-26. Jiménez-Jiménez FJ, García-Ruiz PJ, Molina JA. Drug-induced movement disorders. Drug Saf 1997;16:180-204. Rao AS, Camilleri M. Review article: metoclopramide and tardive dyskinesia. Aliment Pharmacol Ther 2010;31:11-9. Frank S. Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat 2010;6:657-65. Arbaizar B, Gómez-Acebo I, Llorca J. Postural induced-tremor in psychiatry. Psychiatry Clin Neurosci 2008;62:638-45. Koller W, Lang A, Vetere-Overfield B, et al. Psychogenic tremors. Neurology 1989;39:1094-9. Deuschl G, Koster B, Lucking CH, et al. Diagnostic and pathophysiological aspects of psychogenic tremors. Mov Disord 1998;13:294-302. Kim YJ, Pakiam AS, Lang AE. Historical and clinical features of psychogenic tremor: a review of 70 cases. Can J Neurol Sci 1999;26:190-5. Savoiardo M. Differential diagnosis of Parkinson’s disease and atypical parkinsonian disorders by magnetic resonance imaging. Neurol Sci 2003;24(Suppl 1):S35-7. Massano J, Costa F, Nadais GT. Teaching neuroImage: MRI in multiple system atrophy: “hot cross bun” sign and hyperintense rim bordering the putamina. Neurology 2008;71:e38. Hedera P, Fang JY, Phibbs F, et al. Positive family history of essential tremor influences the motor phenotype of Parkinson’s disease. Mov Disord 2009;24: 2285-8. Benito-León J, Louis ED, Bermejo-Pareja F. Neurological Disorders in Central Spain Study Group. Risk of incident Parkinson’s disease and parkinsonism in essential tremor: a population based study. J Neurol Neurosurg, Psychiatry 2009;80:423-5. Fischman AJ, Bonab AA, Babich JW, et al. Rapid detection of Parkinson’s disease by SPECT with altropane: a selective ligand for dopamine transporters. Synapse 1998;29:128-41.

DM, March 2011